Dapsone and clofazimine is a known therapeutically effective combination against various Mycobacterium species. However, anti-tubercular effect of this combination is limited due to the low aqueous solubility of clofazimine and production of toxic metabolites after first pass metabolism of dapsone following oral route of administration. Therefore, the aim of this investigation was to develop poly-(lactide-co-glycolic acid) nanoparticles (DCNPS) of dapsone and clofazimine. Nanoparticles were prepared using emulsion solvent evaporation method. Developed DCNPSs were characterized for particle size, zeta potential (Zp), morphology and in vitro release. Positively charged (Zp 27.4 mV) DCNPSs with uniform spherical shape depicted controlled release of dapsone (82%) and clofazimine (68%) after 24h. DCNPS showed significantly improved in vivo efficacy against Mycobacterium tuberculosis H37Rv strain infected small animal model than that of drug solution (DCS) as bacterial loads in the lungs (Log10 of CFU/g) was reduced to 2.7 ± 0.34 (DCNPS) and 4.9 ± 0.21 (DCS) from 6.8 ± 0.23 (diseased control). In vitro therapeutic doses of dapsone and clofazimine in both DCS and DCNPS were found to be very safe to use following intravenous route of administration. DCNPS offered an effective mean of introducing safe delivery of dapsone and clofazimine systemically with enhanced in vivo efficacy against H37Rv strain of Mycobacterium tuberculosis.